There is an increasing need for agents which are effective against opportunistic mycotic infections by such agents as Cryptococcus spp., Candida spp., Aspergillus spp., Histoplasma spp., Coccidioides spp., Paracoccidioides spp. Blastomyces spp., Fusarium spp., Sporothrix spp., Trichosporon spp., Rhizopus spp., Pseudallescheria spp., dermatophytes, Paeciliomyces spp., Alternaria spp., Curvularia spp., Exophiala spp., Wangiella spp., Penicillium spp., Saccharomyces spp., Dematiaceous fungi and Pneumocystis carinii. The present treatments, i.e., polyenes, such as amphotericin B, cause severe side effects and azoles, such as fluconazole, are only fungistatic. The pneumocandins, which are related to the echinocandins, are cyclic hexapeptides which inhibit cell wall 1,3β-D-glucan synthesis. The pneumocandins have shown potent in vivo activity against Candida spp., Pneumocystis carinii, Aspergillus spp., as well as the other fungal pathogens listed above. However, the pneumocandins, by themselves, have weak activity against Cryptococcus spp.
Combination therapy with antifungal drugs may provide additional options for treating Cryptococcus and other fungal pathogens.
Previous studies have evaluated the efficacy of other pneumocandin derivatives against Cryptococcus neoformans in combination with amphotericin B and fluconazole (Abruzzo et al., Antimicrob. Agents Chemo. 1995, 39:1077-1081 and Bartizal et al., Antimicrob. Agents Chemo. 1995, 39:1070-1076). However, none of these studies have demonstrated the results found using Compound I as the pneumocandin derivative.